1. Field of the Invention
The present invention relates to hydro/organo gelators, and more particularly, the present invention relates to a method for preparing hydro/organo gelators from disaccharide sugars by biocatalysis and their use in enzyme-triggered drug delivery, cosmetic components delivery, and making of templated materials to generate inorganic and soft nanomaterials.
2. Description of the Prior Art
Use of renewable resources for production of valuable chemical commodities is becoming a topic of great interest and an objective of promoting the industrial bio-refinery concept in which a wide array of valuable chemicals, fuel, food, nutraceuticals, and animal feed products all result from the integrated processing of grains, oil seeds, and other biomass materials.1 1Lorenz, P. & Zinke, H. White biotechnology: differences in US approaches? Trends Biotechnol. 23, 570-574 (2005); Business and regulatory news. OECD says industrial biotech not realizing potential. Nat. Biotechnol. 19, 493-494 (2001).
An article by Stephan Harrera2 illustrates that industrial or ‘white’ biotechnology3 is making an increasingly important contribution to the development of a sustainable, biobased economy by an environmental benign approach.4 It uses enzymes and micro-organisms to make products in sectors, such as chemistry, food and feed, paper, textile, and medicine. As opposed to chemical synthesis, enzyme catalysis is highly selective and has been used to generate various specialty chemicals,5 including sugar-based esters.6 2Herrera, S. Industrial biotechnology-a chance at redemption. Nat Biotechnol. 22, 671-675 (2004).3Industrial biotechnology and sustainable chemistry. Royal Belgian Academy of Applied Sciences, Brussels (January 2004).4Eissen, M., Metzger, J. 0., Schmidt, E. & Schneidewind, U. 10 Years after rio-concepts on the contribution of chemistry to a sustainable development. Angew. Chem. Int. Ed 41, 414-436 (2002); Biermann, U. et al. New synthesis with oils and fats as renewable raw materials for the chemical industry. Angew. Chem. Int. Ed. 39, 2206-2224 (2000); Gibson, J. M. et al. Benzene-free synthesis of phenol. Angew. Chem. Int. Ed. 40, 1945-1948 (2001).5Wandrey, C., Liese, A. & Kihumbu, D. Industrial biocatalysis: past, present and future. Org. Process Res. Dev. 4, 286-290 (2000).6Yan, Y., Bornschener, U. T. & Schmid, R. D. Lipase-catalyzed synthesis of vitamin C esters. Biotechnol. Lett. 21, 1051-1054 (1999).
Thus, there exists a need for developing building blocks from renewable resources to generate soft nanomaterials, such as new surfactants, liquid crystals, organic gelling materials, and hydrogels.7 7John, G., Masuda, M. & Shimizu, T. Nanotube formation from renewable resources via coiled nanofibers. Adv. Mater. 13, 715-718 (2001); John, G., Masuda, M., Jung, J. H., Yoshida, K. & Shimizu, T. Unsaturation influenced gelation of aryl glycolipids. Langmuir 20, 2060-2065 (2004); John, G., Mason, M., Ajayan, P. M. & Dordick, J. S. Lipid-based nanotubes as functional architectures with embedded fluorescence and recognition capabilities. J. Am. Chem. Soc. 126, 15012-15013 (2004).
Hydrogels have a range of biomedical applications in areas such as tissue engineering,8 controlled released drug delivery systems,9 and medical implants.10 Design and synthesis of low-molecular-weight hydrogelators has received considerable attention in soft materials research in terms of its potential applications in cosmetics, toiletries, and pharmaceutical formulations. Literature study reveals that there are only limited reports on easily achievable and efficient low-molecular-weight gelators that are able to gel water or even water mixtures with other solvents,11 and which are often achieved by multi-step chemical synthesis. Surprisingly, to the best of applicants' knowledge, to date there are no examples in the literature where low-molecular-weight hydrogelators were synthesized from renewable resources by using regioselective enzyme catalysis. 8Lee, K. Y. & Mooney, D. J. Hydrogels for tissue engineering. Chem. Rev. 101, 1869-1879 (2001).9Friggeri, A., Feringa, B. L. & van Esch, J. Entrapment and release of quinoline derivatives using a hydrogel of low molecular weight gelator. J. Controlled Release 97, 241-248 (2004); Yang, Z., Liang, G., Wang, L. & Xu, B. Using a kinase/phosphatase switch to regulate a supramolecular hydrogel and forming the supramolecular hydrogel in vivo. J. Am. Chem. Soc. DOI:10.1021/j057412y (2006); van Bommel, K. J. C., Stuart, M. C. A., Feringa, B. L. & van Esch, J. Two-stage enzyme mediated drug release from LMWG hydrogels. Org. Biomol. Chem. 3, 2917-2920 (2005).10Lee, K. Y. & Mooney, D. J. Hydrogels for tissue engineering. Chem. Rev. 101, 1869-1879 (2001); Miyata, T., Uragami, T. & Nakamae, K. Biomolecule-sensitive hydrogel. Adv. Drug Delivery Rev. 54, 79-98 (2002).11Menger, F. M. & Caran, K. L. Anatomy of a gel. Amino acid derivatives that rigidify water at submillimolar concentrations. J. Am. Chem. Soc. 122, 11679-11691 (2000); Jokic, M., Makarevic, J., Zinic, M. & Makarevic, J. A novel type of small organic gelators: bis(amido acid) oxalyl amides. J. Chem. Soc., Chem. Commun. 1723-1724 (1995); Makarevie, J. et al. Bis(amino acid) oxalyl amides as ambidextrous gelators of water and organic solvents: supramolecular gels with temperature dependent assembly/dissolution equilibrium. Chem. Eur. J. 7, 3328-3341 (2001); Oda, R., Huc, I. & Candau, S. J. Gemini surfactants as new, low molecular weight gelators of organic solvents and water. Angew. Chem. Int. Ed. 37, 2689-2691 (1998); Estroff, L. A. & Hamilton, A. D. Effective gelation of water using a series of bis-urea dicarboxylic acids. Angew. Chem. Int. Ed. 39, 3447-3450 (2000); Kobayashi, H. et al. Molecular design of “super” hydrogelators: understanding the gelation process of azobenzene-based sugar derivatives in water. Org. Lett. 4, 1423-1426 (2002); Luboradzki, R., Gronwald, O., Ikeda, M., Shinkai, S. & Reinhoudt, D. N. An attempt to predict the gelation ability of hydrogen-bond-based gelators utilizing a glycoside library. Tetrahedron 56, 9595-9599 (2000); Gronwald, 0. & Shinkai, S. Sugar-integrated gelators of organic solvents. Chem. Eur. J. 7, 4328-4334 (2001); Jung, J. H. et al. Self-assembly of a sugar-based gelator in water: Its remarkable diversity in gelation ability and aggregate structures. Langmuir 17, 7229-7232 (2001); Wang, G. & Hamilton, A. D. Low molecular weight organogelators for water. Chem. Commun. 310-311 (2003).
Thus, there exists a need to use biocatalysis as a tool to make gelators from biomass and their assembly to form hierarchical superstructures in water, i.e., formation of hydrogel and soft nanomaterials, encapsulation of hydrophobic drug or hydrophobic cosmetic components, as well as enzyme mediated hydrogel degradation, which will give new insights into low-molecular-weight hydrogelators-based drug delivery.
Controlled delivery of drugs or cosmetic material occurs when a polymer, whether natural or synthetic, is judiciously combined with a drug or other active agent in such a way that the active agent is released in a pre-designed manner.12 While these advantages can be significant, the potential disadvantages cannot be ignored, such as the possible toxicity or non-biocompatibility of the materials used, the undesirable by-products from gel degradation, and the higher cost of controlled-release systems compared with traditional pharmaceutical formulations. 12Dorski, C. M., Doyle, F. J. & Peppas, N. A. Preparation and characterization of glucose-sensitive P(MMA-a-EG)hydrogels. Polym. Mater. Sci. Eng. Proceed. 76, 281-282 (1997); Vert, M., Li, S. & Garreau, H. More about the degradation of LA/GA derived matrices in aqueous media. J. Controlled Release 16, 15-26 (1991).
Thus, there exists a need for sugar amphiphiles by regioselective synthesis of amygdalin esters as new hydrogelators, which are low cost, efficient, safe, and with high gelation efficiency.
[O-β-D-glucopyranosyl-(1-6)-β-D-glucopyranosyloxy]benzeneacetonitrile known as D-Amygdalin is a naturally occurring glycoside found in many food plants, for example, the kernels of apples, almonds, peaches, cherries, and apricots.13 Amygdalin (a by-product of apricot, almonds and peach industry, see FIG. 1, which are pictures of: (a) an apricot pit that is a source of amygdalin; (b) Curcuma longa; and, (c) powdered curcumin14 that is commonly known as turmeric and used in traditional Indian culinary and medicine—has been used as a main ingredient in commercial preparations of laetrile, a purported therapeutic agent.15 13Jones, D. A. Why are so many food plants are cyanogenic? Phytochemistry 47, 155-162 (1998).14Curcumin is just one example as a drug model.15Turczan, J. W. & Medwick, T. Qualitative and quantitative analysis of amygdalin using NMR spectroscopy. Anal. Lett. 10, 581-590 (1977); Syrigos, K. N., Rowlinson-Busza, G. & Epenetos, A. A. In vitro cytotoxicity following specific activation of amygdalin by β-glucosidase conjugated to a bladder cancer-associated monoclonal antibody. Int. J. Cancer 78, 712-719 (1998).
Thus, there exists a need to synthesize amygdalin derivatives that can form nanoaggregates through self-assembly and encapsulation of a hydrophobic drug followed by release of the encapsulated drug upon enzyme mediated degradation, i.e., enzyme-triggered drug-delivery.
In amygdalin-fatty acid conjugates, sugar moiety can facilitate the stacking of molecules through hydrogen bonding, phenyl ring can facilitate intermolecular interactions through π-π stacking, and hydrophobic hydrocarbon chain not only decreases the solubility in water, it also helps the molecular association through the van der Waals interactions.
In general, multi-step synthesis, arduous separation procedures, and lower yields often keep low-molecular-weight gelators away from commercial use due to high production cost. Strikingly, the hydrogelators of the present invention were synthesized from renewable resources in a single-step process in high yields (>90%), and unpurified crude products showed unprecedented gelation abilities like their counter pure products, allowing the development of versatile gelators which can be made from low cost starting materials and without purification.
Thus, there exists a need for gelator molecules with various chain lengths. See FIG. 2, which is a synthetic scheme of amygdalin-based amphiphiles.